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A fork in the road of human brain development

October 27, 2016

Human brain cells begin their lives as pluripotent cells with the potential to develop into any cell type in the body. As those pluripotent stem cells differentiate and mature, forks in the road of their development dictate how, when and where they become a particular type of cell.  Generally, it has been difficult to see the choices made by human brain cells, largely due to their rarity, and because they cannot be studied in living tissue.

To get around this problem, scientists have recently begun mimicking human brain development using pluripotent stem cells in a dish, with the goal of understanding the many nuances that guide the differentiation and development of human brain cells. But one question that has remained unanswered is how well these cells match up to their authentic brain counterparts.


Human neurons grown on mouse astrocytes. Blue marks DNA (all cell nuclei, both human and mouse), green marks human nuclei (looks cyan when overlaid on blue in human nuclei), red marks GFAP, a protein in astrocytes (all the mouse cells), and yellow marks beta-3 tubulin, a protein in neurons (some of the human cells).


To tackle this problem, Allen Institute for Brain Science and Harvard University scientists implemented a new technology to profile the gene expression of single cells generated in the lab, and then compared that data to gene expression data from real brain tissue. This profiling effort led to the identification of 41 cell types throughout the course of differentiation—but researchers noticed that early in development, those 41 cell types were separated into two major groups. Scientists then evaluated the gene expression signatures of these 41 cell types and were able to identify this split as a major developmental moment in which stem cells are sent down one of two distinct paths: to become cells in either the front of the brain or the middle and back of the brain. The work is published this month in the journal Cell Stem Cell.

“This split is important for two reasons,” says Boaz Levi, Ph.D., Assistant Investigator at the Allen Institute for Brain Science. “First, it identifies a crucial moment in the developmental lineage of these stem cell-derived brain cells. But perhaps even more interestingly, this lineage split indicates that our model is producing multiple brain regions, not just one. We hope that by showing not only that this lineage bifurcation occurs, but also that there is a method to toggle the switch on the bifurcating tracks, we can inform and improve other models of human brain differentiation."

“The roadmap of human brain development is extraordinarily complex. By identifying prominent forks, like this distinction between forebrain and mid-hindbrain, we hope to move closer to models that can help us better distill meaning and logic from this complexity,” says Levi.